The Synphora solution
Noise-induced tinnitus generates reactive oxygen species (free radicals) damaging the neural structures which may be involved in tinnitus generation.

Acoustic trauma triggers a cochlear overstimulation which may cause an excess release of glutamate in the synapse between the inner hair cells and the auditory nerve. An up-regulation of NMDA glutamate receptors may also occur. Both processes occurring simultaneously may in turn lead to a massive Ca2+ release of and activation of pro-apoptotic signaling cascades in the spiral ganglion cells and ultimately cell death decreasing auditory nerve activity.

Latanoprost, and other prostaglandin PGF2α analogues, have been shown to a exert neuroprotective effect, e.g. against glutamate toxicity in retinal ganglion cells. This effect is independent of its effect of lowering intra-ocular pressure through activation of the uveoscleral outflow of ocular fluid. A potential suggested mechanism for its neuroprotective effect has been the suppression of Ca2+ and as a consequence apoptosis.

Salicylate-induced tinnitus has been suggested to be due to excessive arachidonic acid levels due to the blockade of COX1-2. The arachidonic acid would then potentiates the effect of glutamate causing a dysregulation of cochlear NMDA receptors. An alternative interpretation is that the reduced levels of cochlear prostaglandin following COX1-2 inhibition may elicit tinnitus assuming that endogenous PGF2α generated in the cochlea, is important for the normal physiologic hearing process.

All three examples provide appealing potential mechanisms of action and rationale for prostaglandin PF2α intervention in noise-induced tinnitus which is currently under evaluation.

Effects of extracochlear gacyclidine perfusion on tinnitus in humans: a case series.Abstract
Gacyclidine, a non-competitive NMDA receptor antagonist, is a phencyclidine derivative with neuroprotective properties. It has been previously safely administered intravenously to acute traumatic brain-injured patients. Experiments in guinea pigs have shown that local administration of gacyclidine to the cochlea can suppress salicylate-induced tinnitus. Thus, we thought that patients with therapy-resistant sensorineural tinnitus might benefit from a local therapy with gacyclidine. As a compassionate treatment, we administered aqueous gacyclidine solution via a Durect RWmuCath(TM) into the round window niche in six patients with unilateral deafness associated with tinnitus. The response of each patient to the drug treatment was given a numerical value by the use of a visual analogue scale (VAS) on a scale of 0-10 for tinnitus intensity, where 0 represented no tinnitus and 10 represented unbearable tinnitus-intensity or -annoyance (subjective). After constant perfusion of gacyclidine for 40-63 h, four out of six patients experienced a temporary relief from their tinnitus. No serious side effects were recorded in any of the cases. Gacyclidine might present a potent drug for the suppression of sensorineural tinnitus in humans and therefore should be considered for future double-blinded, placebo-controlled clinical trials. For lasting effective treatment, controlled intracochlear and long-term delivery of the drug seems to be necessary. Further studies investigating the toxicological effects of gacyclidine intracochlear perfusion as well as different dosages and therapy durations are under way to ensure the safety of the drug for long-term human use and warrant clinical trials.

Change will not come if we wait for some other person or some other time. We are the ones we've been waiting for. We are the change that we seek.
— Barack Obama

Their research looked promising as apparently gacyclidine worked quite well for tinnitus.

Click to expand...

I did research them last month. I don't believe they are still in business, but they just be could off the radar. They were developing a pump to deliver drugs to the inner ear. They had a clinical trial in Belgium and France, but it was terminated. This is usually not a good sign. But inner ear drug delivery systems, including pumps, are still a growing area. Even if NeuroSystec no longer exists, the researchers probably went to other companies also working on these technologies.

Note: This is a California company. Why they went to Europe is interesting. Did they have financial connections in Europe? Or is the climate for clinical trials and drug approval superior in Europe? I do see one of their research partners is the Medical University of Hannover, which is located in Germany.

I believe their technology was a two pronged approach. I haven't read about them in a little while but I think they had a delivery system (the pump) that they had engineered, but were also working on a small molecule for treatment as well. I could never find any information about what the nature of their compound was though.

The Medical University of Hannover, Germany, seems very active in tinnitus research, including their relationship with NeuroSystec. The University is also interested in inner ear delivery systems--again, the same as NeuroSystec. (See Markku's Gacyclidine citation) I wonder what relationship exists between researchers in each organization?

Anyway, inner ear delivery systems are exciting, new areas to treat tinnitus and inner ear diseases. Here are a two of several references:

I believe their technology was a two pronged approach. I haven't read about them in a little while but I think they had a delivery system (the pump) that they had engineered, but were also working on a small molecule for treatment as well. I could never find any information about what the nature of their compound was though.

Click to expand...

Yes, I think I found this drug, but there's not much information on it. This is from the ATA's site:

Tom Lobl, Ph.D.,Vice President of Research and Development for NeuroSystec, a company with the mission to relieve the suffering of patients with hearing and neurological diseases by combining therapeutics and delivery devices to provide new intervention tools for medicine. Also, improve therapeutic profile and reduce side effects through tissue-specific delivery of powerful CNS agents. Tom appears in over 30 publications and holds 15 patents/applications. He and his team are currently developing a novel drug for tinnitus, NST-001.

I actually find this very interesting, it fits into the engineering side of schooling that I've had. That's why I like the look of Sue Shore's lab at UM as well. Now I just need to get off my rear end and take the GRE....

The Medical University of Hannover, Germany, seems very active in tinnitus research, including their relationship with NeuroSystec. The University is also interested in inner ear delivery systems--again, the same as NeuroSystec. (See Markku's Gacyclidine citation) I wonder what relationship exists between researchers in each organization?

Anyway, inner ear delivery systems are exciting, new areas to treat tinnitus and inner ear diseases. Here are a two of several references:

From what i've looked up, Thomas Lobl now works for the Alfred Mann Foundation. The address is the exact same as NeuroSystec. Maybe they just ditched the Neurosystec name and are now inside the AMF. The AMF are interestingly enough a lot into these implants research but nothing on tinnitus on their website.

For the clinical trial, i could be wrong but someone french (have a look at the history changes) may have edited the status of the trial to "Terminated" as "Terminé" means "Completed" in french

From what i've looked up, Thomas Lobl now works for the Alfred Mann Foundation. The address is the exact same as NeuroSystec. Maybe they just ditched the Neurosystec name and are now inside the AMF. The AMF are interestingly enough a lot into these implants research but nothing on tinnitus on their website.

For the clinical trial, i could be wrong but someone french (have a look at the history changes) may have edited the status of the trial to "Terminated" as "Terminé" means "Completed" in french

Click to expand...

Thanks James for all this information! Let's hope "terminated" just meant "completed."

Several weeks ago, when I was critiquing the ATA's inability to fund itself adequately, I came across the AMF. It's a very interesting foundation. There's a potential tie in with tinnitus--especially since it often follows similar neurological pathways as chronic pain. Here's the AMF's research focus from their website:

Movement disorders, diabetes, limb loss and pain are all critical problems patients face today. The Alfred Mann Foundation's goal is to develop medical devices to help patients who have few medical options and advance that technology to the marketplace.
​

More importantly, they helped developed an improved version of a cochlear implant in 1986. AMF is serious money, but, like you, I don't see a current interest in inner ear drug delivery systems. But AMF is interested in electrical stimulation through implants for neuromuscular diseases. That might be why they hired Lobl. Or else he could be working in their chronic pain division, specifically their infusion pumps. Either way, this is a disappointment compared to Neurosystec's research.

But, then again, maybe AMF is interested in tinnitus, but the research is in its early stages. We can only hope. Because if AMF is interested, that could be a game changer for these types of devices.

On another side, have you looked at the synfora website ? Looks nice and maybe promising.

Click to expand...

Yes, I did look into Synfora's interest in noise-induced tinnitus. They are targeting the NMDA receptors in the cochlea--the same as Auris Medical's AM 101. Auris's drug uses the Round Window Membrane to deliver their drug to the cochlea; I presume Synfora would do the same or similar. That's why developing pumps for drug delivery would be superior as you could better control dosing.

As you know, Auris is doing well with their drug. But, so far, the clinical trials are for tinnitus up to three months. But they are willing to extend it to a year in one upcoming phase III trial. This is promising.

Most researchers argue that chronic tinnitus ( > 6 or 12 months) is more challenging to treat than acute tinnitus (< 3 or 6 months). In chronic tinnitus, the brain has memorized the tinnitus sound. What's responsible for this memorization, researchers postulate, is the dorsal cochlear nucleus (DCN). The DCN serves a gatekeeper function for tinnitus in the brain. (For information on the DCN and tinnitus, see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804917)

Synfora mentions the importance of treating tinnitus early--while it is still in the cochlea:

As times passes, the origin of sound-induced tinnitus undergoes a gradual relocation from the cochlea to the auditory brain, a process termed neural plasticity involving a form of re-programming of the brain.

This has implications for the timing of interventional treatments following noise-induced tinnitus. While the tinnitus is still of peripheral and cochlear origin it may still be amenable to treatment via intratympanic injection of drugs stabilizing the cochlear signaling. This may prevent the permanent plasticity changes occurring in the auditory brain which could translate into chronic tinnitus. (http://www.synphora.com/noise-induced-tinnitus/about-noise-induced-tinnitus.html)​

Auris also discusses this with their drug, even though they will expand their time frame. It appears the company feels the window between acute and chronic may be open longer than three months. (See http://www.aurismedical.com/p/therapies/am_101.php)

It's also possible--I'm just speculating--that people with chronic tinnitus will need a two-step approach. First, they will need to treat the damage in the cochlea, such as AM 101's treatment; second, they will need to address the neural correlates of tinnitus. Treating the latter might involve an oral medication or a neuromodulation modality. By addressing both injuries that result in the tinnitus precept, I'm sure the disorder will either be cured or rendered a non-issue, i.e., the noise disappears.

Of course, efficacious treatments for acute tinnitus are equally important for people with chronic tinnitus. Such treatments will prevent further damage from noise or trauma. (I don't know about hearing loss due to aging.) So the future does look bright!

About Novartis' drug: It might still be useful for people with tinnitus. Several anti-epileptic drugs have worked for some tinnitus sufferers, especially carbamazepine and neurontin. It's all about inhibiting overactive neural pathways. I'm sure the drug will be recommended "off label" for people with tinnitus once it's approved for epilepsy and migraine. As physicians develop tinnitus categories based on etiology, not just duration (acute or chronic), different types of treatment will be recommended. At least, this is what several researchers currently argue.

Here is the reply i got from Tom Lobl of ex-NeuroSystec regarding gacyclidine :

Dear Mr. White,

Your enquiry to the AMF has been forwarded to me for response. Unfortunately, NeuroSystec has closed and its assets have been sold to another company. This company is now considering if they want to continue developing gacyclidine or not.

The “in construction” note on the website was added after closure when they wanted to take down the website but the future was not certain. It is still up because the former owners have forgotten about it.

The AMF unfortunately does not have any rights to develop this compound for tinnitus. I would recommend to the AMF that tinnitus is a good market to develop products for but that decision has not been made internally. In any event it could not develop gacyclidine.

Thanks James for investigating the NeuroSystec mystery. I and many others appreciate your efforts!

We'll have to keep monitoring the medical literature to see if gacyclidine appears in new pipeline. It would be a shame if this compound were not developed since it showed promise as a NMDA antagonist, like Auris' AM 101.

This report provides comprehensive information on the therapeutic development for Tinnitus, complete with comparative analysis at various stages, therapeutics assessment by drug target, mechanism of action (MoA), route of administration (RoA) and molecule type, along with latest updates, and featured news and press releases. It also reviews key players involved in the therapeutic development for Tinnitus and special features on late-stage and discontinued projects.

The report enhances decision making capabilities and help to create effective counter strategies to gain competitive advantage. It strengthens R&D pipelines by identifying new targets and MOAs to produce first-in-class and best-in-class products.

Companies Involved in Therapeutics Development

AudioCure Pharma GmbH

Auris Medical Holding AG

Flexion Therapeutics, Inc.

Knopp Biosciences LLC

Merz Pharma GmbH & Co. KgaA

Otonomy, Inc.

Sound Pharmaceuticals, Inc.

Synphora AB

Drug Profiles

acamprosate

AM-102

AUT-00063

AUT-3

Drug to Activate KCNQ for Tinnitus

esketamine hydrochloride

gacyclidine SR

latanoprost

neramexane mesylate

Small Molecules for Tinnitus

Small Molecules to Activate Kv7 for Neuropathic Pain, Epilepsy and Tinnitus

This report provides comprehensive information on the therapeutic development for Tinnitus, complete with comparative analysis at various stages, therapeutics assessment by drug target, mechanism of action (MoA), route of administration (RoA) and molecule type, along with latest updates, and featured news and press releases. It also reviews key players involved in the therapeutic development for Tinnitus and special features on late-stage and discontinued projects.

The report enhances decision making capabilities and help to create effective counter strategies to gain competitive advantage. It strengthens R&D pipelines by identifying new targets and MOAs to produce first-in-class and best-in-class products.

Companies Involved in Therapeutics Development

AudioCure Pharma GmbH

Auris Medical Holding AG

Flexion Therapeutics, Inc.

Knopp Biosciences LLC

Merz Pharma GmbH & Co. KgaA

Otonomy, Inc.

Sound Pharmaceuticals, Inc.

Synphora AB

Drug Profiles

acamprosate

AM-102

AUT-00063

AUT-3

Drug to Activate KCNQ for Tinnitus

esketamine hydrochloride

gacyclidine SR

latanoprost

neramexane mesylate

Small Molecules for Tinnitus

Small Molecules to Activate Kv7 for Neuropathic Pain, Epilepsy and Tinnitus

If members of this forum would like a market review (also available for free), they can alternatively read the following article prepared by The Tinnitus Research Initiative (TRI) which supports Team Trobalt.

I wonder how much progress has been made on the pump delivery system. A little off topic but I remember seeing something about one of the problems of stem cells was that there is no way to directly apply them to the inner ear. If something like a pump could effectively and safely deliver them to the inner ear I wonder if it would be more successful. I only say this because it seems as though the T specific drugs that are targeted at the ear are only for the acute stage.